Hormonal Regulation of Type II Glucocorticoid Receptor Messenger Ribonucleic Acid in Rat Brain*

Abstract

Differences in the regulation of type II glucocorticoid receptor (GR) mRNA levels in female rat brain regions involved in the control of the hypothalamic-pituitary-adrenal axis were studied by Northern blot analysis after chronic administration of corticosterone or dexamethasone to adrenalectomized (ADX), ovariectomized (OVX), and ADX/OVX animals. The effect of chronic estradiol or progesterone treatment of intact animals was also studied. Our results show that type II GR mRNA levels of ADX animals were significantly increased above control values in amygdala (140%) and hippocampus (196%), but not in hypothalamus. These increased transcript levels were down-regulated by corticosterone or dexamethasone, with the exception of those in the amygdala, where corticosterone had no effect. Ovariectomy significantly increased hypothalamic GR mRNA content (174%) over control values, and this increase was sensitive to dexamethasone. The combined effect of adrenalectomy/ovariectomy on GR mRNA levels was greater than that of adrenalectomy only in amygdala. Corticosterone increased amygdala transcript levels in OVX and ADX/OVX animals. Estradiol administration to intact animals raised the GR mRNA content of amygdala, while progesterone treatment had no effect on any of the brain regions studied. We conclude that there exists heterogeneity with respect to type II GR mRNA regulation by corticosterone and dexamethasone in brain regions of ADX female rats, and that certain limbic structures show greater sensitivity to these hormonal manipulations, suggesting a more prominent role in the regulation of the hypothalamic-pituitary-adrenal axis. Our results also suggest that circulating estrogens can influence the sensitivity of brain structures (i.e. hypothalamus and amygdala) to glucocorticoids by altering GR mRNA levels. These regions may represent integration sites at which gonadal steroids are able to alter stress hormone secretion.

Differences in Down-Regulation of Glucocorticoid Receptor mRNA by Cortisol, Prednisolone and Dexamethasone in HeLa Cells.

“…Dexamethasone treatments however, resulted in a consistent decrease of 40-60% in GR mRNA levels in all the tissues studied [13]. Peiffer et al showed GR mRNA levels in the rat increased significantly above control values after adrenalectomy in amygdala and hippocampus and the increased transcript levels were down-regulated by dexamethasone in the same tissues [12]. In contrast, Eisen et al detected an increase in the GR mRNA levels of the glucocorticoid-sensitive human leukemic Tcell line CEM-C7 after as little as 3 h incubation with 1 x 10-6 M dexamethasone, which continued for at least 18 h [22].…”

“…Glucocorticoids down-regulate the levels of their cognate receptors in a number of target tissues and in many differ-ent cell lines [7][8][9]. Autoregulation of GR has been shown to involve both a decrease in the half-life of the GR protein [10] and changes in GR mRNA levels [3, 6,9,[11][12][13][14][15].…”

The Antidepressant Desipramine Requires the ABCB1 (Mdr1)-Type p-Glycoprotein to Upregulate the Glucocorticoid Receptor in Mice

“…The desipramine-induced GR upregulation in the amygdala of abcb1ab (À/À) mice (as opposed to the tendency for a downregulation in the amygdala of FVB/ N controls) is also puzzling, although is consistent with the notion that, as for the hippocampal GR, desipramine have opposite effects on the GR in these two mice groups. GR expression is differently regulated in the hippocampus, cortex, and amygdala, and powerful GR manipulations such as adrenalectomy, glucocorticoid treatment, and programming induce different effects on GR expression in these areas (Meaney et al, 1985;Sapolsky and McEwen, 1985;Pepin et al, 1990;Peiffer et al, 1991a;Welberg et al, 2001), although the molecular mechanisms underlying these localized differences are still unclear.…”

Testosterone Suppression of CRH-Stimulated Cortisol in Men

“…While both testosterone and estradiol modulate glucocorticoid receptor activity in brain regions mediating restraint of the HPA axis (Burgess and Handa, 1992;Carey et al, 1995;Redei et al, 1994;Peiffer et al, 1991), a more parsimonious explanation suggests that the blunted cortisol secretion during testosterone administration results in less restraint on ACTH secretion, consistent with the greatest difference in the cortisol : ACTH ratios between conditions occurring from 120 to 180 min. Similarly, a central action of testosterone or estradiol should appear as increased basal ACTH levels and would not be apparent with exogenous CRH stimulation (or would appear as blunting due to CRH receptor downregulation at the corticotroph).…”